1. Field of the Invention
The present invention broadly concerns a system for delivering small predetermined volumes of liquid preparations to the eye or other parts of the mammalian body. The invention has particular application in performing treatments of the eye in a reproducible and reliable manner.
2. Related Art
There is a need for a practical system for delivering small microliter volumes of medicaments accurately to parts of the mammalian body. This is especially the case in the field of ophthalmology. A single drop of current ophthalmic preparations delivers far more volume than the preocular tear film can hold. The excess volume delivered is either drained via the nasolacrimal drainage system, making it available for systemic absorption, or lost as waste over the eyelid margin. However, only limited attempts have been made to develop reliable and practical small volume delivery systems for the ocular surface.
The lacrimal dynamic and pharmacokinetic differences between large (&gt;30 ml) and small (&lt;30 ml) volumes instilled in the eye have been well characterized. Studies in rabbits have determined that the rate of drainage through the nasolacrinal system is directly proportional to the volume of liquid instilled in the eye (Chrai et al., 1973). The normal preocular tear volume is 7.5-10.0 ml. With normal blinking, the volume can be expanded by another 10 ml without overflow (Chrai et al., 1973). Larger volumes of liquid result in a greater preocular drug loss. Increased volume delivered results in both increased drainage of drug via responses such as reflex tearing, further diluting the drug. This means the rate of drug loss actually increases as the volume of drug instilled increases (Chrai et al., 1974).
Studies in rabbits using micropipettes to deliver ophthalmologically-active drugs suggest the desirability of delivering small liquid volumes to the eye in order to minimize systemic effects and maximize local ocular effects. Pilocarpine, a cholinergic parasympathomimetic agent that is used in the treatment of glaucoma, has ocular effects including constriction of the pupil and lowering of the intraocular pressure (IOP). Unwanted systemic effects of this drug may include intestinal spasm, bronchoconstriction, hypotension, and decreased heart rate. Decreasing the dose of pilocarpine administered to the eye allows equivalent absorption of pilocarpine in the aqueous humor of the eye, lowering the IOP, but decreased pilocarpine concentration in the plasma (Patton and Francoeur, 1978; Himmelstein et al., 1978). Other studies have confirmed the existence of this dose effect regarding medication delivered to the eye. For example, Patton found that decreasing the volume instilled in the eye actually increases the fraction of pilocarpine absorbed into the eye from the preocular tear film (Patton, 1977).
Numerous studies in humans further support the desirability of decreasing the volume of liquid pharmaceuticals delivered to the eye. Smaller ocular doses allow maintenance of the ocular therapeutic effects while decreasing or eliminating undesired systemic effects. These smaller doses have been administered using calibrated micropipettes as delivery devices. Using clonidine, an antihypertensive agent, Petursson et al,, (1984) determined that instilling small volumes of 15 .mu.l to the eye results in separation of the ocular hypotensive effects from the systemic hypotensive effects and equivalent decreases in intraocular pressures as seen with larger volumes. Other authors found that changing the volume of phenylephrine administered to the eye from 32 ml to 10 ml had the same beneficial effect (pupillary dilation) as administering twice the volume, while markedly decreasing systemic absorption and side effects such as increased blood pressure (Brown et. al., 1986). A study in infants using phenylephrine demonstrated that a relatively small volume (8.mu.l) produced equivalent ocular effects and significantly lowered systemic blood levels when compared to a 30 ml dose (Brown et al., 1987). A study with healthy adult volunteers found no enhancement of pupillary constriction with macrodrop versus microdrop volumes of pilocarpine (File and Patton, 1980). These studies indicate the advantages of using small microliter volumes for ocular solutions; however, the problem of reproducible administration of microvolumes of drug has not been addressed.
While several studies have demonstrated the benefits of using small microliters doses of ophthalmic liquids, the mode of delivery (micropipettes) described is of limited use outside of the laboratory. In particular, micropipetting is not a suitable technique for self-administration by patients. No methods have been described which can accurately and reliably deliver small microliter volumes, are reliable and easily manufactured, and are easily manipulated by non-medical personnel and patients.
Current delivery systems use volumes on the order of 30 .mu.l and larger because they cannot reliably deliver smaller volumes. Volumes of 30 .mu.l or more typically result in a large overdose to the eye with systemic effects as the excess drug is absorbed into the circulatory system, and reduced effectiveness and retention time on the ocular surface. The tearing and blinking that accompanies instillation of macrodrops to the eye may cause significant dilution of drug and increased drainage of the drug. Reflex tearing may be in excess of 25 .mu.l per min. Reduced retention time caused by the activation of tearing which may cause the drug to be washed out and drained from the ocular surface. Blinking that can accompany the instillation of a 30-50 .mu.l drop in the eye enhances liquid entry into the nasolacrimal drainage system, thereby increasing the rate of drug loss from the preocular tear film.
Current ophthalmic drug delivery devices also present a substantial problem in that the tip can easily come into contact with the eye or surrounding tissue. This creates a path for contaminants to travel between the delivery device and the eye. This is due in part to the fact that patients tend to hold their heads in an awkward position, thus making it more difficult for them to judge where the dispenser bottle is being held relative to the eye. In addition, contact between the dispenser tip and the eye or adnexa may result in clogging of the tip.
Conventional ophthalmic delivery devices typically deliver a single drop of about 30 .mu.l or more. It is easy to accidentally squeeze the dropper bottle and deliver multiple drops with this dispenser, thus doubling or tripling the dosage with concomitant systemic absorption.
For ophthalmic drugs to be effective, they must be delivered with reasonable reliability to the eye. With current ocular drug delivery systems, it is possible for a patient to miss the eye completely, for example by depositing the drug on the eyelid, and to assume that the drug has been properly delivered. Thus, lack of efficacy may be related to the failure of the delivery system.
The instillation of too large a volume of liquid, 30 .mu.l or more, to the eye may result in a number of phenomena that reduce the efficiency of drug pharmacokinetics. Reflex tearing results in dilution of the delivered volume, and enhances drainage into the nasolacrimal drainage system. Reflex blinking as a result of macrodrop delivery accentuates the reduction in preocular residence time, and enhances drainage through the nasolacrimal drainage system. Use of macrodrops may further cause discomfort, such as burning and stinging, to the user. Thus, the ability to consistently deliver volumes of liquid medicaments as small as 1 ml is a desirable goal.